Project Summary The high prevalence of Alzheimer's disease (AD) in the African American (AA) population has been identified as an emerging health crisis by the Alzheimer's Association. While there is already a disproportionate percentage of African Americans with AD relative to the non-white Hispanic population (20% of all AD cases nationwide), this percentage is expected to increase to 42% of all cases nationwide by 2050. As such, there is an urgent need to address this current and growing health disparity. One of the key hallmarks of AD is tauopathy, the presence of neurofibrillary tangles (NFTs) in brain tissue. NFTs are aggregates of tau, a protein that normally binds to and stabilizes the microtubule network in neurons. The transition from tau's physiological association with the microtubule to the unbound form that leads to NFTs is due to the hyperphosphorylation of tau by a number of cellular kinases. Not only does tau hyperphosphorylation lead to the formation of NFTs, but its dissociation from microtubules leads to their destabilization, with resulting impacts on neuronal transport and organization. Preventing hyperphosphorylation of tau is thus a key target for the development of novel therapeutics for AD. Our project targets the inhibition of casein kinase 1 ?/? that are known to phosphorylate the tau protein at residues involved in microtubule binding. Our laboratory has identified two classes of molecules that inhibit casein kinase 1?/?, blocking tau phosphorylation in cell-based assays. The goal of this proposal is to optimize these lead compounds to potential therapeutics with increased potency. Computational molecular modeling tools will be used to design new derivatives that will be synthesized using organic synthetic methods. To determine the efficacy of these new compounds in the inhibition of CK1?/?, we will test them in a reconstituted biochemical assay of tau phosphorylation using purified components. The end products of these assays will also be subjected to microtubule affinity assays to show that inhibiting CK1-dependent phosphorylation of tau maintains the physiologically relevant role of tau and blocks the pathological development of NFTs. The compounds developed through this process can serve as potential therapeutics for AD after further pre-clinical and clinical testing. This project will capitalize on the existing RCMI infrastructure that has been established at Xavier University of Louisiana, one of the nation's premier HBCUs for STEM education and research.